“Urinary incontinence” is a condition, perceived objectively, in which urine leaks involuntary, and is both a social and a hygienic problem (J. Clin. Pharm. Ther., 25(4), 251-263 (2000)). Typical types of urinary incontinence are urge urinary incontinence, stress urinary incontinence, and mixed urinary incontinence, which is a mixture of the two types.
The most common type of urinary incontinence is stress urinary incontinence, and about 50% of women who suffer urinary incontinence reportedly have stress urinary incontinence (Int. Urogynecol. J., 11(5), 301-319 (2000)). “Stress urinary incontinence” is a condition in which urine leaks involuntarily, regardless of contraction of the bladder, with elevated abdominal pressure associated with coughing, sneezing, movement, or the like. The causes of stress urinary incontinence are divided mainly between two causes. One cause is bladder neck and urethral hypermobility, in which transmission of abdominal pressure to the urethra is poor due to the bladder neck dropping based on relaxation of the pelvic floor muscle, and when abdominal pressure rises, intravesical pressure rises without increased urethral pressure pressure, causing urine to leak. Another cause is reduced sphincter function due to intrinsic urethral sphincter insufficiency, causing urine to leak with increased abdominal pressure. The onset of stress urinary incontinence is very likely related to embrittlement of the pelvic floor muscle and/or reduced sphincter function due to age or childbirth. In particular, trauma to the pelvis due to pregnancy or vaginal birth is a known risk factor for onset of persistent stress urinary incontinence, and the incidence of stress urinary incontinence within 5 years after first childbirth is reportedly about 30% (Neurourol. Urodyn., 21(1), 2-29 (2002)).
“Urge urinary incontinence” is a condition in which urine leaks involuntarily following a sudden, irresistible strong urge to urinate (urinary urgency). “Mixed urinary incontinence” is a condition in which different types of urinary incontinence occur, and in most cases is a mixture of urge urinary incontinence and stress urinary incontinence.
Urinary incontinence has a major impact on quality of life (QOL). Patients acutely aware of the symptoms of incontinence have a restricted range of activity, and feel socially isolated and lonely.
Drugs reported to have a therapeutic effect on stress urinary incontinence are drugs having a serotonin-norepinephrine reuptake inhibiting effect (SNRI), drugs having a selective norepinephrine reuptake inhibiting effect (NRI), and the like. Sudden increase in abdominal pressure and intravesical pressure found with coughing, sneezing, movement, or the like contracts the external urethral sphincter through spinal reflex, but norepinephrine and serotonin increases excitability of the intraspinal Onuf's nucleus, which is the nucleus of origin of the somatic motor nerve governing the external urethral sphincter. Specifically, SNRI and NRI medications reportedly excite the pudendal nerve comprising the somatic motor nerve and increase contraction of the external urethral sphincter by accelerating excitability of the Onuf's nucleus (Non-patent Documents 1 and 2).
Although the SNRI duloxetine was reportedly effective on stress urinary incontinence in a clinical study, undesirable adverse drug reactions such as suicide attempts were reported. The country where duloxetine is approved as an urinary incontinence therapeutic agent is restricted to only Europe. Although the NRI nisoxetine, in a preclinical study, reportedly increased urethra internal pressure and improved incontinence induced by sneezing (Non-patent Document 2), no clinical study has been carried out for stress urinary incontinence. The NRI (S,S)-reboxetine reportedly increased urethral resistance in a clinical study, and is reportedly effective for stress urinary incontinence (Non-patent Documents 3 and 4), but has not yet been received pharmaceutical marketing approval as a urinary incontinence therapeutic agent.
Drugs having an al-receptor agonist effect contract the urethra through al-receptors present in urethral smooth muscle and have been shown in a clinical study to be effective on stress urinary incontinence, but have not yet received pharmaceutical marketing approval as a stress urinary incontinence therapeutic agent due to cardiovascular adverse drug reactions such as elevated blood pressure (Non-patent Document 5).
As noted earlier, raising urethral resistance to maintain control of urinary incontinence seems to be effective as a drug therapy for stress urinary incontinence, and drugs based on several mechanisms of action have been studied. Due to problems such as adverse drug reactions, however, no urinary incontinence therapeutic agent has been approved globally, and development of a stress urinary incontinence therapeutic agent based on a novel mechanism of action would be greatly desirable.
The external urethral sphincter and the pelvic floor muscle which supports the structures related to the bladder and urethra and the like are types of skeletal muscle. Myofibrils, which are the contractile organ of skeletal muscle, link together units called sarcomeres comprising thin actin filaments and fat actin filaments. Skeletal muscle contracts by an actin filament and a myosin filament interacting repeatedly such that the two filaments slide past each other.
The contractile response of skeletal muscle is caused by release of calcium ions from intracellular sarcoplasmic reticula according to excitation of the somatic motor nerve governing each skeletal muscle. Intracellular calcium ions binding to a troponin complex, which is one component protein of an actin filament, changes the structure of the troponin complex to allow the actin filament to interact with a myosin filament. Thus, the troponin complex functions in the actin filament as a regulator protein mediating a contractile response of the skeletal muscle which is dependant on the concentration of calcium ions.
Skeletal muscles are classified as fast-twitch muscles and slow-twitch muscles, where fast muscles are functionally characterized by a faster contractile rate with greater muscle tension than slow muscles. Troponin complexes combine different isoforms of troponin in fast and slow muscles to form fast- and slow-muscle troponin complexes.
Drugs having fast skeletal muscle troponin activation are known to act on fast-muscle troponin complexes to increase the sensitivity of the troponin complexes to intracellular calcium ions so as to increase the contractile force of fast muscles (Non-patent Document 6).
1-[2-({[Trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl]methyl}amino)pyrimidin-5-yl]-1H-pyrrole-3-carboxamide (hereafter also called “compound A”) is a compound having fast skeletal muscle troponin activation (Patent Document 1). Compound A has been shown to shift the concentration-response curve of intracellular calcium ions concentration and muscle tension to the left in rat diaphragm myofibrils and rat extensor digitorum longus muscle including a fast-muscle component (Patent Document 2, 3). Compound A also reportedly has actions reinforcing the contractile response of a rat diaphragm induced in vitro by transmural electrical stimulation, and reinforcing extensor digitorum longus muscle contractile response by electrical stimulation of the rat fibular nerve in vivo (Patent Document 2, 3).
The external urethral sphincter and the pelvic floor muscle are skeletal muscles which reportedly include a fast-muscle component (Non-patent Document 7, 8).